Adult: To improve exercise capacity and symptoms, and to decrease clinical deterioration in patients with WHO functional class II-IV symptoms: <40 kg: 62.5 mg bid. ≥40 kg: Initially, 62.5 mg bid for 4 weeks. Maintenance dose: 125 mg bid. Dose reduction, interruption, or discontinuation may be required according to individual safety or tolerability (refer to detailed product guidelines). Child: To improve pulmonary vascular resistance (PVR) in paediatric patients with idiopathic or congenital PAH: ≥3-≤12 years ≥ 4-8 kg: 16 mg bid; >8-16 kg: 32 mg bid; >16-24 kg: 48 mg bid; >24-40 kg: 64 mg bid. >12 years Same as adult dose. Dosing recommendations may vary among individual products and between countries (refer to specific product guidelines).
Oral Systemic sclerosis with ongoing digital ulcer disease
Adult: To reduce the number of new digital ulcers: Initially, 62.5 mg bid for 4 weeks. Maintenance dose: 125 mg bid. Treatment recommendations may vary among individual products and between countries (refer to specific product guidelines).
Special Patient Group
Patient with ALT/AST levels of >3 times but ≤5 times ULN: If the result is confirmed by another aminotransferase test, reduce the daily dose or interrupt treatment. Monitor aminotransferase levels at least every 2 weeks. May continue or reintroduce treatment if aminotransferase levels return to pre-treatment values.
Patient with ALT/AST levels of >5 times but ≤8 times ULN: If the result is confirmed by another aminotransferase test, stop treatment and monitor aminotransferase levels at least every 2 weeks. May reintroduce treatment if aminotransferase levels return to pre-treatment values.
Patient with ALT/AST levels of >8 times ULN: Stop treatment and do not reintroduce.
Hepatic Impairment
Pulmonary arterial hypertension
Moderate to severe (Child-Pugh class B and C) and/or baseline transaminase >3 times upper limit of normal (ULN): Contraindicated.
Administration
May be taken with or without food.
Reconstitution
Disperse tablets for oral susp in a minimal amount of water immediately before administration.
Contraindications
Women of childbearing potential who are not using reliable methods of contraception. Moderate to severe hepatic impairment (Child-Pugh class B or C). Pregnancy. Concomitant use with ciclosporin and glibenclamide.
Special Precautions
Patient with underlying heart failure due to potential complications from fluid retention. Children. Lactation.
Adverse Reactions
Significant: Fluid retention, peripheral oedema, decreased haematocrit/Hb (dose-related), elevated transaminase (ALT or AST ≥3 times ULN), hypersensitivity reactions (e.g. anaphylaxis, angioedema, rash, drug reaction with eosinophilia and systemic symptoms). Rarely, unexplained liver cirrhosis in patients with multiple comorbidities and drug therapies (prolonged use); liver failure. Blood and lymphatic system disorders: Anaemia. Cardiac disorders: Palpitations. Gastrointestinal disorders: GERD, diarrhoea. Nervous system disorders: Headache, syncope. Respiratory, thoracic and mediastinal disorders: Nasal congestion. Skin and subcutaneous tissue disorders: Erythema. Vascular disorders: Flushing, hypotension.
Women of childbearing potential must use 2 reliable methods of contraception.
Monitoring Parameters
Monitor serum transaminases (ALT, AST) and bilirubin at baseline then monthly thereafter, or as clinically necessary; Hb and haematocrit at baseline, after 1 and 3 months of treatment, and every 3 months thereafter. Obtain pregnancy tests prior to initiation of therapy, monthly during treatment, and 1 month after treatment discontinuation. Monitor for signs and symptoms of liver injury and fluid retention.
May increase plasma concentration with CYP2C9 inhibitors (e.g. fluconazole, amiodarone), CYP3A4 inhibitors (e.g. ketoconazole, itraconazole, ritonavir, erythromycin, diltiazem), tacrolimus and sirolimus. May decrease plasma concentration of hormonal contraceptives, warfarin, simvastatin, tadalafil and sildenafil. Decreased plasma concentration with rifampicin. Potentially Fatal: Increased plasma concentration with ciclosporin. Enhanced hepatotoxic effect with glibenclamide.
Action
Description: Mechanism of Action: Bosentan, an endothelin receptor antagonist, improves exercise capacity and haemodynamic in patients with pulmonary arterial hypertension (PAH) by blocking endothelin-1 (ET-1) receptors, ETA and ETB (with a slightly higher affinity for subtype A) on vascular endothelium and smooth muscle, thus promoting vasodilation. Pharmacokinetics: Absorption: Absorbed from the gastrointestinal tract. Bioavailability: Approx 50%. Time to peak plasma concentration: 3-5 hours. Distribution: Volume of distribution: Approx 18 L. Plasma protein binding: >98%, mainly to albumin. Metabolism: Metabolised in the liver by CYP2C9 and CYP3A4. Excretion: Via faeces (as metabolites); urine (<3% as unchanged drug). Elimination half-life: Approx 5 hours.
Chemical Structure
Bosentan Source: National Center for Biotechnology Information. PubChem Compound Summary for CID 104865, Bosentan. https://pubchem.ncbi.nlm.nih.gov/compound/Bosentan. Accessed June 27, 2022.
Storage
Store between 20-25°C. Store divided dispersible tab pieces in the opened blister for up to 7 days.
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